Newly discovered VEXAS syndrome may affect thousands more Americans than previously thought

The patient, Hector Campos, presented to the emergency department with shortness of breath, erratic fever, and swollen, itchy ears. His wife explained that Campos had tested negative for COVID-19. “What do you think this could be?” Campos asked emergency room chief Ethan Choi, who was also confused by the man’s symptoms.

Scary, right? But it’s not real – Campos and Choi are both characters in NBC’s medical drama Chicago med. During the course of the episode, which aired in March 2021, Choi initially misdiagnoses Campos’s symptoms as pneumonia and a bacterial infection, but a test comes back for widespread inflammation. Campos’ condition is rapidly deteriorating and the team of doctors are mystified until fellow ER surgeon Dean Archer suggests it could be VEXAS, a rare autoinflammatory syndrome. Genetic sequencing eventually finds a mutation that confirms the diagnosis, and Choi begins treating the patient.

The episode is fictional, but images like this one are surprisingly accurate for real cases of VEXAS, said David Beck, a researcher in clinical genetics at New York University Grossman School of Medicine. “In terms of clinical manifestations,” he told The Daily Beast, “they were perfect.” Beck should know: He and his colleagues first named the syndrome in a study published in The New England Journal of Medicine in 2020. “I am actually impressed by images in popular media, because [it shows] they have read the newspaper.”

Yet these representations of VEXAS syndrome tend to emphasize severe cases, in part because the NEJM paper did, too. Of the 25 cases the researchers studied, 10 of the patients died of VEXAS-related causes.

But more recent research has expanded the case definition of VEXAS to include a milder side. In an article published in JAMA on Jan. 24, Beck and colleagues scanned genetic sequencing measurements from more than 160,000 people to determine how common VEXAS syndrome really is and how symptoms manifest in patients. The research team found that nine male patients and two female patients in their study had mutations that caused VEXAS.

And as a result, the researchers estimate that the syndrome affects about 13,200 men and 2,300 women over the age of 50 in the U.S. alone.

“It’s exciting to go from trying to understand a few patients to discovering that the same genetic cause and the same disease is found in tens of thousands of individuals,” Beck said. “Not just because we know that there are a lot of patients who are suffering, not getting a diagnosis, or not getting the treatment that can help them and just taking a step in that direction; it is also very surprising that despite all the biomedical research you can still make these kinds of discoveries.”

VEXAS is an acronym that stands for several key features of the syndrome. In each case of the syndrome, a patient has a genetic mutation that codes for the enzyme E1. The mutation occurs on a gene on the X chromosome, which, as you may remember from biology class, is a sex chromosome – men only have one, making them more susceptible to VEXAS. And the mutation is somatic, meaning it is acquired during life rather than being inherited from a parent. That last feature, which gives VEXAS its “S,” is crucial: Because VEXAS is caused by a somatic mutation, the syndrome isn’t passed on and occurs only in older patients, usually over age 50, Beck said.

This kind of research, Beck stressed, has been made possible by recent advances in genetic sequencing, making it readily available and affordable for patients. The study participants all sought care at a Geisinger health care facility in central and northeastern Pennsylvania between 1996 and 2022. regions of their genomes that code for proteins – were sequenced.

I’m actually impressed with images in popular media because [it shows] they read the newspaper.

David Beck, New York University Grossman School of Medicine

All 11 participants found to have mutations in the gene for the E1 enzyme were anemic, and the vast majority had abnormally large red blood cells and low platelet counts — all symptoms consistent with VEXAS syndrome. Importantly, however, some of the more serious symptoms associated with VEXAS, such as inflammation in the cartilage (which caused Campos’ swollen ears), were not present in these patients. This suggests that there may be a broader spectrum of severity when it comes to cases of VEXAS syndrome.

Another puzzling aspect of the study was the fact that the two women who were retrospectively identified as having VEXAS syndrome only had the VEXAS-related mutation on a of their X chromosomes, not both. “It’s confusing to us,” because the researchers originally thought VEXAS only affected men, Beck said. “We’ve been slowly recognizing more females who have the disease, and we don’t understand why that is.” One phenomenon at play could be X inactivation, a process by which one of a woman’s two X chromosomes is silenced in their cells.

The researchers wrote in the study that future analyzes will be critical to understanding the prevalence of the syndrome in diverse populations, as 94 percent of participants in the Geisinger cohort were white.

Currently, no treatments for VEXAS have been approved by the Food and Drug Administration, but a phase II clinical trial is underway to investigate whether blood stem cell transplants can treat or cure the syndrome. In 2022, a team of French researchers published a study suggesting that such a transplant can lead to complete remission, but such a procedure is not without risks.

On the research side, Beck said scientists are still trying to figure out how a mutation in the gene that codes for E1 leads to the widespread inflammation seen in cases of VEXAS. This enzyme starts a process for a cell to eliminate proteins it no longer needs, and further research is underway to determine how a dysfunctional E1 enzyme affects this process.

“If you are an older person with systemic inflammation, low blood cell counts, no clear diagnosis, and you need steroids but no clear diagnosis,” you should talk to your doctor about genetic testing for VEXAS syndrome, he said. Beck.

“It may help lead to better treatments for you — and at least a clear diagnosis,” he said.

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